MÁS ALLA DE LA PRIMERA LÍNEA: SECUENCIA DE TRATAMIENTO Dra. Ruth Vera Complejo Hospitalario de Navarra
GOALS Prolongation of survival Cure Improving tumour-related symptoms Stopping tumour progression And/or Quality of life
CONTINNIUM OF CARE Arnold D. ESMO 2016
TREATMENT DECISIONS PRETREATMENT SEQUENCE?
Backbone of first Chemotherapy Fluoropiridin-based chemotherapy: Oxaliplatin Irinotecan Similar activity Both partners for biological agents Different toxicity profile FOLFIRI FOLFOX R FOLFOX FOLFIRI Tournigand C, et al. J Clin Oncol 2004;22:229 237
BEST SEQUENCE? No data of sequence trials but 2 nd Line trials EPIC, 181, TML, VELOUR, RAISE 1 st Line trials (analyzing 2L) FIRE-3, PEAK, CALGB
Anti-Angiogenic treatment Anti-Angiogenic
ML18147 study design (phase III) BEV + standard firstline CT (either oxaliplatin or irinotecan-based) (n=820) PD Randomise 1:1 CT switch: Oxaliplatin Irinotecan Standard second-line CT (oxaliplatin or irinotecan-based) until PD BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-based) until PD Irinotecan Oxaliplatin Primary endpoint Secondary endpoints included Stratification factors Overall survival (OS) from randomisation Progression-free survival (PFS) Best overall response rate Safety First-line CT (oxaliplatin-based, irinotecan-based) First-line PFS ( 9 months, >9 months) Time from last BEV dose ( 42 days, >42 days) ECOG PS at baseline (0/1, 2) Study conducted in 220 centres in Europe and Saudi Arabia
OS estimate OS: TML study 1.0 CT (n=410) BEV + CT (n=409) 0.8 0.6 0.4 0.2 0 Unstratified a HR: 0.81 (95% CI: 0.69 0.94) p=0.0062 (log-rank test) Stratified b HR: 0.83 (95% CI: 0.71 0.97) p=0.0211 (log-rank test) 9.8 mo 11.2 mo 0 6 12 18 24 30 36 42 48 No. at risk Time (months) CT 410 293 162 51 24 7 3 2 0 BEV + CT 409 328 188 64 29 13 4 1 0 Median follow-up: CT, 9.6 months (range 0 45.5); BEV + CT, 11.1 months (range 0.3 44.0) a Primary analysis method; b Stratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS ( 9 months, >9 months), time from last dose of BEV ( 42 days, >42 days), ECOG performance status at baseline (0, 1)
BEBYP study design (phase II) Masi et al. Ann Oncol 2015
Masi et al. Ann Oncol 2015
ANTIANGIOGENIC TREATMENT Arnold & Tabernero, Oncolpathol 2013
VELOUR Phase III Trial in Second-line Metastatic Colorectal Cancer 600 pts Aflibercept 4 mg/kg IV + FOLFIRI q 2 weeks Patients with metastatic colorectal cancer after failure of an oxaliplatinbased regimen R 1:1 600 pts DISEASE PROGRESSION DEATH STRATIFICATION FACTORS: Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) Placebo + FOLFIRI q 2 weeks PRIMARY ENDPOINT: OS SECONDARY ENDPOINTS: ORR, PFS, safety, PK Van Cutsem et al, J Clin Oncol 2012;30:3499-3506. 1 4
OS: VELOUR study 6-Month Interval OS Hazard Ratios (Piecewise Cox Proportional Hazard Model) Time (months) HR (95.34% CI) vs Placebo/FOLFIRI t 6 0.860 (0.664-1.114) 6 <t 12 0.838 (0.673-1.043) 12 <t 18 0.782 (0.582-1.050) t >18 0.676 (0.463-0.988) 1. Van Cutsem et al, J Clin Oncol 2012;30:3499-3506. 2. Ruff P. et al. Eur J Cancer. 2015; 51(1): 18-26
Tabernero et al, GI Cancer Symposium 2015
Ramucirumab: Ensayo RAISE Tabernero J, et al. Lancet Oncol 2015; 16:499.
Wirapati, P. (2017, Mayo) VELOUR trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity Poster presentado en ASCO Chicago, USA.
Arnold D. ESMO 2016
Arnold D. ESMO 2016
ANTI-angiogenic treatment Anti-EGFR
ERBITUX + irinotecan (n=648) Irinotecan (n=650) Hazard ratio p-value ORR 16% 4% - <0.0001 PFS meses 4.0 2.6 0.69 0.0001 OS, meses 10.7 10.0 0.975 0.71 20% K-ras 47% CET 13% BV previo Sobrero AF, et al. J Clin Oncol 2008;26:2311 2319
Metastatic CRC (n=1186) R 1:1 Stratification by: ECOG score: 0-1 vs. 2 Prior oxaliplatin exposure for mcrc FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W*) FOLFIRI (Q2W*) Prior bevacizumab exposure for mcrc Study endpoints: PFS/OS (co-1 ); ORR, safety, HRQoL E n d o f t r e a t m e n t L o n g t e r m f o l l o w u p Peeters M, et al. J Clin Oncol 2010; 28:4706-13.
Progression-free probability Progression-free probability PFS (KRAS WT, Prior Bevacizumab Treatment) Prior Bevacizumab 1 Primary Analysis 2 100 1.0 80 0.8 60 0.6 40 0.4 20 0.2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 0 0 2 4 6 8 10 12 14 16 18 20 Months Months Events n (%) Median (95% CI) months Events n (%) Median (95% CI) months Panitumumab+ FOLFIRI (n=55) 31 (56) 5.8 (5.2 6.7) Panitumumab+ FOLFIRI (n=303) 178 (59) 5.9 (5.5 6.7) FOLFIRI (n=60) 46 (77) 3.7 (3.5 5.3) FOLFIRI (n=294) 203 (69) 3.9 (3.7 5.3) HR=0.71 (95% CI: 0.45 1.13) p-value=0.150 HR=0.73 (95% CI: 0.59 0.90) p-value=0.004 2.0 1. Peeters M, et al. J Clin Oncol 2011; 29(Suppl):3574 (poster presentation); 2. Peeters M, et al. J Clin Oncol 2010; 28:4706-13. * Analysis based upon the primary analysis data set
SPIRITT Trial FOLFIRI + Panitumumab or Bevacizumab in 2 nd -line Treatment of KRAS WT mcrc (Open Label, Phase 2) mcrc after failure of 1 st -line ox-based CT with bevacizumab ( 4 doses) (n=182) R 1:1 FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W) FOLFIRI (Q2W) + bevacizumab 5 mg/kg or 10 mg/kg (Q2W) (Institutional standard dose) Stratification by: Reason for 1 st -line treatment failure (progression vs. toxicity) Intended bevacizumab dose (5mg/kg vs. 10 mg/kg) Tumour assessment Q8W Treatment administered until progression, death or withdrawal from study Study endpoint: PFS* (1 ); OS, ORR, TTP, safety, exploratory biomarker analysis *PFS, progression-free survival; defined as time from date of randomisation to date of first radiographic disease (per modified RECIST v1.0), or death within 60 days after the last evaluable tumour assessment or randomisation (whichever is later). Subjects not meeting the criteria by the cut-off date were censored at the last evaluable tumour assessment date; OS, overall survival; ORR, objective response rate; TTP, time to progression Hecht JR, et al. J Clin Oncol 2013; 30(Suppl 34):454 (poster)
Survival Probability (%) Proportion Event-Free (%) SPIRITT Trial PFS and OS ORR: 32% vs 19% PFS OS 100 90 80 Panitumumab + FOLFIRI (n=91) Bevacizumab + FOLFIRI (n=91) 100 90 80 Panitumumab + FOLFIRI (n=91) Bevacizumab + FOLFIRI (n=91) 70 HR=1.01 (95%CI: 0.68 1.50) 70 HR=1.06 (95%CI: 0.75 1.49) 60 60 50 50 40 40 30 30 20 20 10 10 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Months 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Months Hecht JR, et al. J Clin Oncol 2013; 30(Suppl 34):454 (poster).
PRODIGE-18 trial Hiret et al, ASCO 2016
Anti-EGFR treatment -----Anti-angiogenic treatment
STRATEGIC-1: GERCOR Arnold D. ESMO 2016
SEQUENCE: TTD
Recommendation 20: Second-line combinations with targeted agents Patients who are bevacizumab naïve should be considered for treatment with an antiangiogenic (bevacizumab or aflibercept) second-line [I, A]. The use of aflibercept should be restricted to combination with FOLFIRI for patients progressing on an oxaliplatin-containing regimen [I, A]. Patients who received bevacizumab first-line should be considered for treatment with: Bevacizumab post-continuation strategy [I, A] Aflibercept or ramucirumab (in combination with FOLFIRI) when treated in first line with oxaliplatin [I, A] EGFR antibodies in combination with FOLFIRI/irinotecan for patients with RAS wild-type (BRAF wild-type) disease Relative benefit of EGFR antibodies is similar in later lines compared with second-line [II, A]. Patients who are fast progressors on first-line bevacizumab-containing regimens, should be considered for treatment with aflibercept or ramucirumab (only in combination with FOLFIRI) [II, B], and - in the case of patients with RAS wild-type disease and no pre-treatment with anti-egfr therapy - EGFR antibody therapy, preferably in combination with chemotherapy [II, B].